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Pistoia Alliance European Conference 2015 - Stefan Klostermann / Roche

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Pistoia Alliance European Conference 2015 - Stefan Klostermann / Roche

  1. 1. The HELM Antibody Editor Stefan Klostermann Roche Innovation Center Penzberg Pistoia Alliance Spring Conference, Zürich, 14. April 2015
  2. 2. Agenda • The motivation for • The HELM Antibody Editor • DEMO: From raw sequences to drugs
  3. 3. Classical chemistry • Aspirin • Acetylsalicylic acid SMILES O=C(Oc1ccccc1C(=O)O)C InChI 1S/C9H8O4/c1-6(10)13-8-5-3-2-4- 7(8)9(11)12/h2-5H,1H3,(H,11,12)
  4. 4. A more biological example Conjugate of peptide and DNA oligo • Peptide CHRISTIAN with Ser replaced by dSer • linked via SMCC (bifunctional linker) • to oligo CTAG
  5. 5. Classical chemical notations Full molecular structure - SMILES • [H]N[C@@H](CSC(=O)C1CCC(CN 2C(=O)CC(OC[C@H]3O[C@@H]([ C@H](O)[C@@H]3OP(O)(=O)OC[C @H]3O[C@@H]([C@H](O)[C@@H ]3OP(O)(=O)OC[C@H]3O[C@@H]( [C@H](O)[C@@H]3OP(O)(=O)OC[ C@H]3O[C@@H]([C@H](O)[C@@ H]3O[H])N3C=NC4=C3N=C(N)NC 4=O)N3C=NC4=C3N=CN=C4N)N 3C=C(C)C(=O)NC3=O)N3C=CC(N )=NC3=O)C2=O)CC1)C(=O)N[C@ @H](CC1=CNC=N1)C(=O)N[C@ @H](CCCNC(N)=N)C(=O)N[C@@ H]([C@@H](C)CC)C(=O)N[C@H]( CO)C(=O)N[C@@H]([C@@H](C)O )C(=O)N[C@@H]([C@@H](C)CC)C (=O)N[C@@H](C)C(=O)N[C@@H] (CC(N)=O)C(O)=O
  6. 6. PEPTIDE1{C.H.R.I.[dS].T.I.A.N}|CHEM1{[SMCC]}|RNA1{R(C)P.R(T)P.R(A)P.R(G)} $RNA1,CHEM1,1:R1-1:R2|PEPTIDE1,CHEM1,1:R3-1:R1$$$ HELM Notation and editor views of given example PEPTIDE1{C.H.R.I.[dS].T.I.A.N}|CHEM1{[SMCC]}|RNA1{R(C)P.R(T)P.R(A)P.R(G)} $RNA1,CHEM1,1:R1-1:R2|PEPTIDE1,CHEM1,1:R3-1:R1$$$ • Limited set of biological building blocks is packed into monomer library • Notation supports homology searching (a least on natural analogues)
  7. 7. HELM Background • Hierarchical Editing Language for Macromolecules – Notation – HELM Editor & Toolkit • Released by Pfizer to the for public distribution – http://openhelm.org/  Github • Emerging new notation standard for complex biologicals
  8. 8. Agenda • The motivation for • The HELM Antibody Editor • DEMO: From raw sequences to drugs
  9. 9. 1 2 3 4 HELM for Antibodies • Why antibodies? – Highly potent and specific drugs especially in Oncology / Immunology • What makes antibodies a bit special? – Multiple peptide chains – Intra- + inter- chain Cys-Cys bonds – Added functional modules / payloads – Varying complex designs – Designed mutations LC HC LC HC
  10. 10. HELM Antibody Editor to handle complex antibodies • Analysis / decomposition • Visualization • Manipulation • Registration
  11. 11. • Detection, analysis and annotation of all domains • Cys-Cys bonds – Intra-domain (Ig-like) – Inter-domains (scFv, scFab) – Inter-chains (HC-HC/LC) – Alert if free Cys left HELM Antibody Editor Decomposition & Assembly • Variable, hinge, constant • V: germlines, C: isotypes • Species ( human?) • Mutations (knob-into-hole) • Peptides, linkers, payloads bispecific trispecific effector protein knob-into-hole Xmab
  12. 12. HELM Antibody Editor Enable Registration & Data Analysis Enable registration • Unique identifier (check) • Full chemical structure • Domains & annotations • Antibody format (used modules) • Antibody depiction • Goal: Fully automatic even starting with raw sequences! Data analysis 1) SAR analysis of • Specificities • Antibody formats • Linker types/lengths • Payloads (+position) 2) Retrieval of components 2 1 3
  13. 13. Agenda • The motivation for • The HELM Antibody Editor • DEMO: From raw sequences to drugs
  14. 14. DEMONSTRATION HELM Antibody Editor
  15. 15. HELM HELM Editor view of demoed complex antibody drug
  16. 16. Role of HELM for the HELM Antibody Editor • HELM Notation used for registration PEPTIDE1{C.H.R.I.[dS].T.I.A.N}|CHEM1{[SMCC]}|RNA1{R(C)P.R(T)P.R(A)P.R(G)} $RNA1,CHEM1,1:R1-1:R2|PEPTIDE1,CHEM1,1:R3-1:R1$$$ • HELM Toolkit used for coding • HELM Editor used for manipulations of domains (e.g. for ADCs)
  17. 17. Summary The HELM Antibody Editor • enables an easy (usually automatic) registration of even complex antibody formats – for SAR analysis within and across projects – and full search & retrieval of all components. • has been made public in the tradition of the HELM Editor and is available now at https://github.com/PistoiaHELM/HELMAntibodyEditor.
  18. 18. Acknowledgements To the developers Domain editor and framework (Pharma Research and Early Development Informatics, Roche Innovation Center Penzberg, Germany) • Pandu Raharja (Trainee) • Stefan Zilch (BridgingIT GmbH, Mannheim) • Marco Lanig (quattro research GmbH, Martinsried) • Clemens Wrzodek (Roche pREDi, Penzberg) Domain recognition (quattro research GmbH, Martinsried, Germany Bernhard Schirm, project lead) • Anne Mund (Trainee) • Marco Lanig
  19. 19. Doing now what patients need next

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